Session Title: Rheumatoid Arthritis: Animal Models
Session Type: Abstract Submissions (ACR)
Background/Purpose: The aim of the study was to examine the role of IL-7 in the pathogenesis of rheumatoid arthritis (RA) as well as in collagen induced arthritis (CIA).
Methods: Linear regression analysis was employed to correlate expression of IL-7 and IL-7R with levels of DAS28 score in RA monocytes. Next, the contribution of IL-7/IL-7R to RA synovial fluid induced monocyte migration was examined by in vitro chemotaxis. Finally, CIA mice were treated therapeutically with IgG or anti-IL-7 antibodies and clinical parameters, joint proinflammatory factors, % spleen TH-1 and TH-17 cells as well as markers of bone destruction were quantified employing ELISA, FACS analysis or real-time RT-PCR.
Results: We show that patients with higher disease activity express elevated levels of IL-7 (R2=0.54, p=2.10×10-14) and IL-7R (R2=0.56, p=6.59×10-15) in 76 RA monocytes suggesting that ligation of IL-7 to IL-7R may be associated with disease progression. Next, experiments were performed to determine whether IL-7 and its receptor play a role in RA synovial fluid mediated monocyte migration. We found that neutralization of IL-7 in RA synovial fluid or blockade of IL-7R on monocytes greatly suppressed RA synovial fluid-mediated monocyte migration further documenting the importance of IL-7 and IL-7R function in myeloid cells. In order to evaluate whether IL-7 is a potential target in RA pathogenesis, CIA, a chronic murine model of RA was employed. We show that like in RA, IL-7R is significantly elevated in the lining and sublining macrophages as well as in sublining endothelial cells in CIA compared to PBS treated ankles. Additionally CIA mice produce 3 fold higher joint IL-7 levels compared to the control group. Hence to examine the role of IL-7/IL-7R in CIA pathology, CIA mice were therapeutically treated with anti-IL-7 antibody or IgG control starting on day 26 post CIA induction. These studies demonstrate that anti-IL-7 antibody treatment significantly reduced joint inflammation on days 33, 37, 40, 41 and 42 post CIA induction compared to the control group however there were no differences detected between the two treatment groups on days 28 and 30. We next found that joint TNF-a as well as ankle and serum levels of CCL2/MCP-1 were 2 fold higher in the IgG group compared to anti-IL-7 antibody treated CIA mice. We also demonstrate that anti-IL-7 treatment was capable of markedly reducing expression of markers for CIA bone erosion including RANKL (3 fold) and Cathepsin K (10 fold). In contrast the percentage of CD3, CD4, TH-1 and TH-17 positive cells was similar in anti-IL-7 and IgG treatment groups. Consistent with these findings joint IL-6 levels were unaffected by anti-IL-7 therapy while there was a trend towards lower levels of joint IL-1b and IL-17 however these values were not significantly different among the two treatment groups.
Conclusion: These novel results suggest for the first time that ligation of IL-7 to IL-7R can affect cell migration, production of proinflammatory factors and osteoclast differentiation from myeloid cells in RA as well as in experimental arthritis models.
N. D. Chamberlain,
S. J. Kim,
N. J. Sweiss,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/il-7-an-important-pro-inflammatory-factor-that-affects-myeloid-cell-function-in-ra-and-cia/